Validation of an algorithm for automated classification of migraine and tension-type headache attacks in an electronic headache diary

Background: This study evaluates the accuracy of an automated classification tool of single attacks of the two major primary headache disorders migraine and tension-type headache used in an electronic headache diary. Methods: One hundred two randomly selected reported headache attacks from an electronic headache-diary of patients using the medical app M-sense were classified by both a neurologist with specialisation in headache medicine and an algorithm, constructed based on the ICHD-3 criteria for migraine and tension-type headache. The level of agreement between the headache specialist and the algorithm was compared by using a kappa statistic. Cases of disagreement were analysed in a disagreement validity assessment. Result: The neurologist and the algorithm classified migraines with aura (MA), migraines without aura (MO), tension-type headaches (TTH) and non-migraine or non-TTH events. Of the 102 headache reports, 86 cases were fully agreed on, and 16 cases not, making the level of agreement unweighted kappa 0.74 and representing a substantial level of agreement. Most cases of disagreement (12 out of 16) were due to inadvertent mistakes of the neurologist identified in the disagreement validity assessment. The second most common reason (3 out of 16) was insufficient information for classification by the neurologist. Conclusions: The substantial level of agreement indicates that the classification tool is a valuable instrument for automated evaluation of electronic headache diaries, which can thereby support the diagnostic and therapeutic clinical processes. Based on this study’s results, additional diagnostic functionalities of primary headache management apps can be implemented. Finally, future research can use this classification algorithm for large scale database analysis for epidemiological studies

Methylprednisolone blocks interleukin 1 beta induced calcitonin gene related peptide release in trigeminal ganglia cells

Background Methylprednisolone (MPD) is a rapid acting highly effective cluster headache preventive and also suppresses the recurrence of migraine attacks. Previously, we could demonstrate that elevated CGRP plasma levels in a cluster headache bout are normalized after a course of high dose corticosteroids. Here we assess whether MPD suppresses interleukin-1β (IL-1β)- and prostaglandin E2 (PGE2)-induced CGRP release in a cell culture model of trigeminal ganglia cells, which could account for the preventive effect in migraine and cluster headache. Metoprolol(MTP), a migraine preventive with a slow onset of action, was used for comparison. Methods Primary cultures of rat trigeminal ganglia were stimulated for 24 h with 10 ng/ml IL-1β or for 4 h with 10 μM PGE2 following the exposure to 10 or 100 μM MPD or 100 nM or 10 µM MTP for 45 min or 24 h. CGRP was determined by using a commercial enzyme immunoassay. Results MPD but not MTP blocked IL-1β-induced CGRP release from cultured trigeminal cells. PGE2-stimulated CGRP release from trigeminal ganglia cell culture was not affected by pre-stimulation whether with MPD or MTP. Conclusion MPD but not MTP suppresses cytokine (IL-1β)-induced CGRP release from trigeminal ganglia cells. We propose that blockade of cytokine mediated trigeminal activation may represent a potential mechanism of action that mediates the preventive effect of MTP on cluster headache and recurrent migraine attacks

Methylprednisolone blocks interleukin 1 beta induced calcitonin gene related peptide release in trigeminal ganglia cells

Background Methylprednisolone (MPD) is a rapid acting highly effective cluster headache preventive and also suppresses the recurrence of migraine attacks. Previously, we could demonstrate that elevated CGRP plasma levels in a cluster headache bout are normalized after a course of high dose corticosteroids. Here we assess whether MPD suppresses interleukin-1β (IL-1β)- and prostaglandin E2 (PGE2)-induced CGRP release in a cell culture model of trigeminal ganglia cells, which could account for the preventive effect in migraine and cluster headache. Metoprolol(MTP), a migraine preventive with a slow onset of action, was used for comparison. Methods Primary cultures of rat trigeminal ganglia were stimulated for 24 h with 10 ng/ml IL-1β or for 4 h with 10 μM PGE2 following the exposure to 10 or 100 μM MPD or 100 nM or 10 µM MTP for 45 min or 24 h. CGRP was determined by using a commercial enzyme immunoassay. Results MPD but not MTP blocked IL-1β-induced CGRP release from cultured trigeminal cells. PGE2-stimulated CGRP release from trigeminal ganglia cell culture was not affected by pre-stimulation whether with MPD or MTP. Conclusion MPD but not MTP suppresses cytokine (IL-1β)-induced CGRP release from trigeminal ganglia cells. We propose that blockade of cytokine mediated trigeminal activation may represent a potential mechanism of action that mediates the preventive effect of MTP on cluster headache and recurrent migraine attacks

HIT-6 and EQ-5D-5L in patients with migraine: assessment of common latent constructs and development of a mapping algorithm

Objective: The aims of this study were to assess whether there is a conceptual overlap between the questionnaires HIT-6 and EQ-5D and to develop a mapping algorithm allowing the conversion of HIT-6 to EQ-5D utility scores for Germany. Methods: This study used data from an ongoing randomised controlled trial for patients suffering from migraine. We assessed the conceptual overlap between the two instruments with correlation matrices and exploratory factor analysis. Linear regression, tobit, mixture, and two-part models were used for mapping, accounting for repeated measurements, tenfold cross-validation was conducted to validate the models. Results: We included 1010 observations from 410 patients. The EQ-5D showed a substantial ceiling effect (47.3% had the highest score) but no floor effect, while the HIT-6 showed a very small ceiling effect (0.5%). The correlation between the instruments' total scores was moderate (- 0.30), and low to moderate among each domain (0.021-0.227). The exploratory factor analysis showed insufficient conceptual overlap between the instruments, as they load on different factors. Thus, there is reason to believe that the instruments' domains do not capture the same latent constructs. To facilitate future mapping, we provide coefficients and a variance-covariance matrix for the preferred model, a two-part model with the total HIT-6 score as the explanatory variable. Conclusion: This study showed that the German EQ-5D and the HIT-6 lack the conceptual overlap needed for appropriate mapping. Thus, the estimated mapping algorithms should only be used as a last resort for estimating utilities to be employed in economic evaluations

Indirect Comparison of Topiramate and Monoclonal Antibodies Against CGRP or Its Receptor for the Prophylaxis of Episodic Migraine: A Systematic Review with Meta-Analysis

Background: Head-to-head comparator trials between first-line oral migraine preventatives and the new monoclonal antibodies (mAbs) blocking the calcitonin gene-related peptide (CGRP) pathway have not been published to date. Objectives: This study aimed to indirectly compare the clinical efficacy and safety of mAbs against CGRP or its receptor (CGRPR) and topiramate in episodic migraine prophylaxis using meta-analysis. Methods: We included controlled trials testing efficacy and safety of erenumab, galcanezumab, fremanezumab, eptinezumab, and topiramate in adults diagnosed with episodic migraine. We searched PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from January 2000 to November 2020. We used the Risk of Bias 2 (RoB2) tool to assess the risk of bias and report pooled mean effects (mean difference and risk ratio) as estimated in a random effect model. For efficacy analysis, we determined the reduction of monthly migraine days (MMDs), reduction of days with acute medication (AMDs), and 50% responder rates (50% RR). For safety, we determined adverse events (AEs) occurring in >= 2% of study participants and the number of patients who discontinue treatment due to AEs (DAEs). The number needed to treat (NNT) and to harm (NNH) were estimated as well as the likelihood to help or harm (LLH). Results: We included 13 trials involving 7557 patients: three trials with erenumab, two trials with galcanezumab, two trials with fremanezumab, one trial with eptinezumab, and five trials with topiramate, for the prophylaxis of episodic migraine in adults. The placebo-subtracted reduction (pooled mean difference) of MMDs were - 1.55 (95% CI - 1.86 to - 1.24; active drug n = 3326 vs placebo n = 2219, 8 studies) for the CGRP(R) mAb and - 1.11 (95% CI - 1.62 to - 0.59; active drug n = 1032 vs placebo n = 543, 4 studies) for topiramate (p for subgroup difference = 0.15). 'Cognitive' and 'sensory & pain'-related adverse events occurred more often in patients treated with topiramate compared with those treated with a CGRP(R) mAb (p for subgroup difference 0.03 and < 0.001, respectively). Based on the 50% RR and DAE, the NNT, NNH, and LHH for the CGRP(R) mAbs were 6, 130, and 24.3:1, respectively. For topiramate, these values were 7, 9, and 1.8:1, respectively. Conclusion: The efficacy of CGRP(R) mAbs to reduce migraine days does not differ from topiramate. However, the safety profile is in favor of the CGRP(R) mAbs, with a higher likelihood to help than to harm compared with topiramate. The diversity of endpoint determination and the heterogeneity between studies for some endpoints cause some limitations for this study

Two TRPV1 receptor antagonists are effective in two different experimental models of migraine

Background The capsaicin and heat responsive ion channel TRPV1 is expressed on trigeminal nociceptive neurons and has been implicated in the pathophysiology of migraine attacks. Here we investigate the efficacy of two TRPV1 channel antagonists in blocking trigeminal activation using two in vivo models of migraine. Methods Male Sprague–Dawley rats were used to study the effects of the TRPV1 antagonists JNJ-38893777 and JNJ-17203212 on trigeminal activation. Expression of the immediate early gene c-fos was measured following intracisternal application of inflammatory soup. In a second model, CGRP release into the external jugular vein was determined following injection of capsaicin into the carotid artery. Results Inflammatory up-regulation of c-fos in the trigeminal brain stem complex was dose-dependently and significantly reduced by both TRPV1 antagonists. Capsaicin-induced CGRP release was attenuated by JNJ-38893777 only in higher dosage. JNJ-17203212 was effective in all doses and fully abolished CGRP release in a time and dose-dependent manner. Conclusion Our results describe two TRPV1 antagonists that are effective in two in vivo models of migraine. These results suggest that TRPV1 may play a role in the pathophysiological mechanisms, which are relevant to migraine

Patients’ and Health Care Workers’ Perception of Migraine Images on the Internet: Cross-sectional Survey Study

Background: The representation of migraine in the media is stereotypical. Standard images of migraine attacks display stylish young women holding their head in a pain pose. This representation may contribute to the social stigmatization of patients with migraine. Objective: We aimed to analyze how patients with migraine and health care workers perceive online images of migraine. Methods: The study consisted of an anonymous web-based survey of patients with migraine at the Headache Center of Charite - Universitatsmedizin Berlin (migraine group) and employees and students at our university (health care group). A total of 10 frequently used Adobe Stock photos of migraine attacks were presented to the participants. Each photo was rated on a scale of 0% to 100% based on how closely it resembled a realistic migraine attack (realism score). Patients with migraine also indicated how much each photo corresponded to their own experience of migraine as a percentage (representation score). We calculated the mean realism and representation scores for all photos and conducted further analyses using the categories male or female models, younger or older models, and unilateral or bilateral pain pose. Results: A total of 367 patients with migraine and 331 health care employees and students completed the survey. In both groups, the mean realism score was <50% (migraine group: 47.8%, SD 18.3%; health care group: 46.0%, SD 16.2%). Patients with migraine identified their own migraine experience in these photos to a lesser degree (mean representation score 44.4%, SD 19.8%; P<.001 when compared to the realism score). Patients and health care workers considered photos with male models to be more realistic than photos with females (P<.001) and photos with older models to be more realistic than those with younger people (P<.001). In the health care group only, a bilateral pain posture was deemed more realistic than a unilateral pose (P<.001). Conclusions: Standard images of migraine attacks are considered only slightly or moderately realistic by patients and health care workers. Some characteristics perceived as more realistic such as male sex or older age are in contrast with migraine epidemiology. A more accurate representation of migraine in the media could help to raise awareness for migraine and reduce the associated stigma

Primary headaches during the COVID-19 lockdown in Germany: analysis of data from 2325 patients using an electronic headache diary

Background Lockdown measures due to the COVID-19 pandemic have led to lifestyle changes, which in turn may have an impact on the course of headache disorders. We aimed to assess changes in primary headache characteristics and lifestyle factors during the COVID-19 lockdown in Germany using digital documentation in the mobile application (app) M-sense. Main body We analyzed data of smartphone users, who entered daily data in the app in the 28-day period before lockdown (baseline) and in the first 28 days of lockdown (observation period). This analysis included the change of monthly headache days (MHD) in the observation period compared to baseline. We also assessed changes in monthly migraine days (MMD), the use of acute medication, and pain intensity. In addition, we looked into the changes in sleep duration, sleep quality, energy level, mood, stress, and activity level. Outcomes were compared using paired t-tests. The analysis included data from 2325 app users. They reported 7.01 +/- SD 5.64 MHD during baseline and 6.89 +/- 5.47 MHD during lockdown without significant changes (p > 0.999). MMD, headache and migraine intensity neither showed any significant changes. Days with acute medication use were reduced from 4.50 +/- 3.88 in the baseline to 4.27 +/- 3.81 in the observation period (p < 0.001). The app users reported reduced stress levels, longer sleep duration, reduced activity levels, along with a better mood, and an improved energy level during the first lockdown month (p <= 0.001). In an extension analysis of users who continued to use M-sense every day for 3 months after initiation of lockdown, we compared the baseline and the subsequent months using repeated-measures ANOVA. In these 539 users, headache frequency did not change significantly neither (6.11 +/- 5.10 MHD before lockdown vs. 6.07 +/- 5.17 MHD in the third lockdown month, p = 0.688 in the ANOVA). Migraine frequency, headache and migraine intensity, and acute medication use were also not different during the entire observation period. Conclusion Despite slight changes in factors that contribute to the generation of headache, COVID-19-related lockdown measures did not seem to be associated with primary headache frequency and intensity over the course of 3 months

Deterioration of headache impact and health-related quality of life in migraine patients after cessation of preventive treatment with CGRP(−receptor) antibodies

Background Migraine preventive treatment with CGRP(-receptor) monoclonal antibodies (mAbs) has a positive effect on patients' health-related quality of life (HRQoL). The German treatment guidelines recommend discontinuing successful treatment with CGRP(-receptor) mAbs after 6-12 months. We aimed to evaluate headache-specific and generic HRQoL for three months after discontinuation of CGRP(-receptor) mAb treatment. Methods We conducted a prospective, longitudinal cohort study, including patients with migraine after 8-12 months of therapy with a CGRP(-R) mAb and before a planned discontinuation attempt. HRQoL was assessed at the time of the last mAbs injection (V1), eight weeks later (V2), and sixteen weeks later (V3). For headache-specific HRQoL, we used the Headache Impact Test-6 (HIT-6). Generic HRQoL was determined with the EuroQol-5-Dimension-5-Level (ED-5D-5L) form, and the Short-Form 12 (SF-12), which comprises a Physical Component Summary (PCS-12) and a Mental Component Summary (MCS-12). Questionnaires' total scores were compared across the three observation points using nonparametric procedures. Results The study cohort consisted of n = 61 patients (n = 29 treated with the CGRP-receptor mAb erenumab and n = 32 with the CGRP mAbs galcanezumab or fremanezumab). The HIT-6 sum score was 59.69 +/- 6.90 at V1 and increased by 3.69 +/- 6.21 at V3 (p < 0.001), indicating a greater headache impact on patients' lives. The mean total EQ-D5-L5 score declined from 0.85 +/- 0.17 at V1 by - 0.07 +/- 0.18 at V3 (p = 0.013). Both Mental and Physical Component Scores of the SF-12 worsened significantly during treatment discontinuation: The PCS-12 total score decreased by - 4.04 +/- 7.90 from V1 to V3 (p = 0.013) and the MCS-12 score by - 2.73 +/- 9.04 (p = 0.003). Changes in all questionnaires' scores but the MCS-12 were already significant in the first month of the drug holiday (V2). Conclusions Our results show a significant decline in headache impact and generic HRQoL of migraine patients after treatment discontinuation of a CGRP(-R) mAb. The observed deterioration is above the established minimally clinically important differences for each of the questionnaires and can therefore be considered clinically meaningful. Monitoring HRQoL during a discontinuation attempt could facilitate the decision whether or not to resume preventive treatment with CGRP(-R) mAbs

Primary trigeminal afferents are the main source for stimulus-induced CGRP release into jugular vein blood and CSF

Abstract Background: Administration of inflammatory soup (IS) leads to a significant release of calcitonin gene-related peptide (CGRP). Whether IS-induced CGRP release originates in primary or secondary neurons of the trigeminovascular system has not been clarified. Methods: We determined CGRP release into the external jugular vein and in cerebrospinal fluid (CSF) following intracisternal IS administration using an in vivo rat model. We further performed polymerase chain reaction (PCR) and immunohistochemistry of the trigeminal ganglion and brainstem (trigeminal nucleus caudalis). To further elucidate a primary vs. secondary origin, experiments were repeated after neonatal capsaicin treatment (NCT) as this treatment destroys primary trigeminal afferents. Results: IS-induced CGRP release into the external jugular vein and CSF were significantly reduced after NCT in both compartments but inhibition was more pronounced in jugular vein blood than in CSF. Baseline CGRP levels were not affected by NCT. PCR results show that following NCT, CGRP mRNA was significantly reduced in the trigeminal ganglion but not in the brainstem. Immunohistochemistry of the TG and brainstem support these results. Conclusions: We conclude that resting state CGRP levels can be maintained after trigeminal denervation of the meninges. However, for functional purposes primary trigeminal afferents are mandatory as they are the major source for stimulusinduced CGRP release